Management of uveal melanoma: a consensus-based provincial clinical practice guideline.

INTRODUCTION: Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. METHODS: A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. RESULTS: Eighty-four publications, including five existing guidelines, formed the evidence base. SUMMARY: Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

Humans and chimpanzees differ in their cellular response to DNA damage and non-coding sequence elements of DNA repair-associated genes.

Compared to humans, chimpanzees appear to be less susceptible to many types of cancer. Because DNA repair defects lead to accumulation of gene and chromosomal mutations, species differences in DNA repair are one plausible explanation. Here we analyzed the repair kinetics of human and chimpanzee cells after cisplatin treatment and irradiation. Dot blots for the quantification of single-stranded (ss) DNA repair intermediates revealed a biphasic response of human and chimpanzee lymphoblasts to cisplatin-induced damage. The early phase of DNA repair was identical in both species with a peak of ssDNA intermediates at 1 h after DNA damage induction. However, the late phase differed between species. Human cells showed a second peak of ssDNA intermediates at 6 h, chimpanzee cells at 5 h. One of four analyzed DNA repair-associated genes, UBE2A, was differentially expressed in human and chimpanzee cells at 5 h after cisplatin treatment. Immunofluorescent staining of gammaH2AX foci demonstrated equally high numbers of DNA strand breaks in human and chimpanzee cells at 30 min after irradiation and equally low numbers at 2 h. However, at 1 h chimpanzee cells had significantly less DNA breaks than human cells. Comparative sequence analyses of approximately 100 DNA repair-associated genes in human and chimpanzee revealed 13% and 32% genes, respectively, with evidence for an accelerated evolution in promoter regions and introns. This is strikingly contrasting to the 3% of DNA repair-associated genes with positive selection in the coding sequence. Compared to the rhesus macaque as an outgroup, chimpanzees have a higher accelerated evolution in non-coding sequences than humans. The TRF1-interacting, ankyrin-related ADP-ribose polymerase (TNKS) gene showed an accelerated intraspecific evolution among humans. Our results are consistent with the view that chimpanzee cells repair different types of DNA damage faster than human cells, whereas the overall repair capacity is similar in both species. Genetic differences in non-coding sequence elements may affect gene regulation in the DNA repair network and thus contribute to species differences in DNA repair and cancer susceptibility.

Microarray mRNA expression analysis of Fanconi anemia fibroblasts.

Fanconi anemia (FA) cells are generally hypersensitive to DNA cross-linking agents, implying that mutations in the different FANC genes cause a similar DNA repair defect(s). By using a customized cDNA microarray chip for DNA repair- and cell cycle-associated genes, we identified three genes, cathepsin B (CTSB), glutaredoxin (GLRX), and polo-like kinase 2 (PLK2), that were misregulated in untreated primary fibroblasts from three unrelated FA-D2 patients, compared to six controls. Quantitative real-time RT PCR was used to validate these results and to study possible molecular links between FA-D2 and other FA subtypes. GLRX was misregulated to opposite directions in a variety of different FA subtypes. Increased CTSB and decreased PLK2 expression was found in all or almost all of the analyzed complementation groups and, therefore, may be related to the defective FA pathway. Transcriptional upregulation of the CTSB proteinase appears to be a secondary phenomenon due to proliferation differences between FA and normal fibroblast cultures. In contrast, PLK2 is known to play a pivotal role in processes that are linked to FA defects and may contribute in multiple ways to the FA phenotype: PLK2 is a target gene for TP53, is likely to function as a tumor suppressor gene in hematologic neoplasia, and Plk2(-/-) mice are small because of defective embryonal development.

Control of the photosynthetic electron transport by PQ diffusion microdomains in thylakoids of higher plants.

We investigate the role of plastoquinone (PQ) diffusion in the control of the photosynthetic electron transport. A control analysis reveals an unexpected flux control of the whole chain electron transport by photosystem (PS) II. The contribution of PSII to the flux control of whole chain electron transport was high in stacked thylakoids (control coefficient, CJ(PSII) =0.85), but decreased after destacking (CJ(PSII)=0.25). From an 'electron storage' experiment, we conclude that in stacked thylakoids only about 50 to 60% of photoreducable PQ is involved in the light-saturated linear electron transport. No redox equilibration throughout the membrane between fixed redox groups at PSII and cytochrome (cyt) bf complexes, and the diffusable carrier PQ is achieved. The data support the PQ diffusion microdomain concept by Lavergne et al. [J. Lavergne, J.-P. Bouchaud, P. Joliot, Biochim. Biophys. Acta 1101 (1992) 13-22], but we come to different conclusions about size, structure and size distribution of domains. From an analysis of cyt b6 reduction, as a function of PSII inhibition, we conclude that in stacked thylakoids about 70% of PSII is located in small domains, where only 1 to 2 PSII share a local pool of a few PQ molecules. Thirty percent of PSII is located in larger domains. No small domains were found in destacked thylakoids. We present a structural model assuming a hierarchy of specific, strong and weak interactions between PSII core, light harvesting complexes (LHC) II and cyt bf. Peripheral LHCII's may serve to connect PSII-LHCII supercomplexes to a flexible protein network, by which small closed lipid diffusion compartments are formed. Within each domain, PQ moves rapidly and shuttles electrons between PSII and cyt bf complexes in the close vicinity. At the same time, long range diffusion is slow. We conclude, that in high light, cyt bfcomplexes located in distant stromal lamellae (20 to 30%) are not involved in the linear electron transport.

[Bilateral chylothorax--case report and literature review]. / Doppelseitiger Chylothorax--Kasuistik und Literaturübersicht.

A bilateral chylothorax developed in a woman patient during recurrence of a non-Hodgkin's lymphoma, originally treated by laminectomy and telecobalt irradiation. Almost simultaneously there was a thrombosis of the brachial vein in the right arm. On the basis of this particular case, attention is drawn to the difficulty in pathogenetic classification. The possible causes, especially of the bilateral nature of the chylothorax, are discussed while referring to the relevant literature.

Subtle neurological injuries in pelvic fractures.

Eleven of 28 patients with a fracture of the acetabulum, pelvis, or sacrum were found to have electromyographic changes, apparently due to injury to the lumbosacral plexus. There appears to be a higher incidence associated with sacral fracture or sacroiliac separation (64%) than with acetabular fracture (24%). The EMG changes are diffuse and the clinical manifestations are subtle but the changes do interfere with the rehabilitation process.

Inhibition of cholesterol synthesis in rat liver by physiological doses of taurocholate.

This report deals with the controversial problem whether bile acids exert a direct inhibitory effect on the rate of hepatic cholesterol synthesis. For this purpose rats have been provided with an 'extracorporeal bile duct', an experimental model which makes it possible to initiate a bile fistula two weeks after last surgery. In the animals that recovered completely from operative trauma, a 6-h infusion of 33.4 mumol sodium taurocholate x (100 g body weight)-1 x h-1, prevented the threefold rise of hepatic cholesterol synthesis following bile diversion. The rate of cholesterol synthesis was monitored by incorporation of [14C] acetate in vitro. There was no difference whether the animals were infused from 4--10 h (dark/light transition) or from 16--22 h (light/dark transition) besides the fact that taurocholate caused a more extensive inhibition during the light-dark transition. A parallel kind of response was observed for the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34), the regulatory enzyme of cholesterol synthesis. A twofold rise of hepatic fatty acid synthesis was observed following bile diversion which was not seen in case of simultaneous bile salt infusion. It is concluded that bile salts exert direct feedback inhibition of hepatic cholesterol synthesis and that opposite results reported by other investigators are probably due to the infusion of too low doses of taurocholate.

A sonic tool for spinal fusion.

The application of sonic energy to bone cutting problems is reported. The basic principle of the resonant tool, its adaptation for surgery, the experimental results of its use in animals, and clinical experience are reported. This sonic tool is found to introduce no significant tissue destruction. It does have several desirable characteristics for routine use in orthopedics.

Salvage of complicated open fractures by transfixation.

The use of a commercially available Reduction-Retention apparatus for transfixation of nine cases of open fractures with severe soft-tissue damage is reported. Seven patients are walking, two with drop foot braces. Two required amputations, one because of infection and the other because he had suffered severe vascular injury. These two are walking on protheses and are able to work. Of the other seven, five have returned to their previous occupations; one is receiving a disability pension and the other is awaiting further surgery. The problems and advantages of this method of treatment are discussed.